title: Anti-CD3-activated killer T cells: Interleukin-6 modulates the induction of major histocompatibility complex-unrestricted cytotoxicity and the expression of genes coding for cytotoxic effector molecules.
abstract: We have investigated the role of interleukin-6 (IL-6) in the induction of major histocompatibility complex (MHC)-unrestricted cytotoxicity, as well as granzyme B, perforin, and Fas ligand gene expression, following mouse T lymphocyte activation with anti-CD3 monoclonal antibody (mAb). The generation of anti-CD3-activated killer-T (AK-T) cells was inhibited when anti-IL-6 neutralizing mAb was added at initiation of culture but not 24 h later, indicating that IL-6 is involved at an early stage of AK-T cell development. However, AK-T cell induction in the presence of exogenous IL-6 did not result in enhanced cytotoxicity, suggesting that saturating levels of IL-6 are normally synthesized in AK-T cell cultures. The inhibitory effect of IL-6 neutralization on AK-T cell generation could not be attributed to a defect in AK-T cell proliferation or to an inability of AK-T cells to recognize and adhere to P815 tumor target cells. However, IL-2 synthesis and CD25 expression were downregulated in AK-T cell cultures performed in the presence of anti-IL-6 mAb. In addition, IL-6 neutralization resulted in decreased expression of granzyme B and perforin, but not Fas ligand, mRNA. Exogenous IL-2 (50 U/ml) added at initiation of culture completely reversed the inhibitory effect of anti-IL-6 mAb on AK-T cell development, restoring CD25 expression and tumoricidal activity, as well as granzyme B and perforin mRNA expression, to control levels. We conclude that IL-6 modulates AK-T cell induction through an IL-2-dependent mechanism.
authors.affiliation: Department of Microbiology and Immunology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: A L
authors.initials: AL
authors.lastname: Greene
authors.forename: A P
authors.initials: AP
authors.lastname: Makrigiannis
authors.forename: L
authors.initials: L
authors.lastname: Fitzpatrick
authors.forename: D W
authors.initials: DW
authors.lastname: Hoskin
mesh_terms: D000818:Animals; D017252:CD3 Complex / Q000276:immunology*; D002460:Cell Line; D005260:Female; D015870:Gene Expression; D005815:Genetic Code; D053804:Granzymes; D007376:Interleukin-2 / Q000502:physiology; D015850:Interleukin-6 / Q000235:genetics / Q000502:physiology*; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D008285:Major Histocompatibility Complex / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D012697:Serine Endopeptidases / Q000096:biosynthesis; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D017252:CD3 Complex; D007376:Interleukin-2; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D015375:Receptors, Interleukin-2; D054353:Perforin; D053804:Granzymes; C509214:Gzmb protein, mouse; D012697:Serine Endopeptidases